This proposal is a revised version of one that was originally submitted under the "FIRST Award" program. The overall objective of this study is to explore the fundamental chemical reactivity of strained ring compounds, particularly the radical-induced fragmentation of epoxides, and to utilize the chemistry for the synthesis of several important natural products. The proposal describes the development of many new and synthetically useful ring-forming reactions that are based on of this facile fragmentation. Through "pilot studies" we have already demonstrated that the process can be exploited to advantage for the construction of useful bicyclic compounds. In the first part of the project, the basic chemistry of these fragmentation reactions will be studied with the aim to develop a better fundamental understanding of the scope and limitation of the chemistry. Several interesting variations of the basic process will be studied, including (a) methods for preparation of enantiomerically pure compounds, (b) the reactivity of aziridine and cyclopropane systems, (c) new methods for generating omicron-quinodimethanes, and (d) methods for functionalizing the initial radical site. The thrust of the research effort will be on the application of the key reaction in the total synthesis of biologically important compounds. In particular, we will utilize this reaction sequence as the key step in an efficient synthesis of the cardiac steroid digitoxigenin, the aglycone of digitoxin, one of the most widely used drugs for the treatment of congestive heart disease. Compounds in this class, however, exhibit severe toxicity, so the need for more effective therapeutic agents is great. In our strategy, the bulk of the steroid skeleton will be constructed in enantiomerically pure form by an intramolecular Diels-Alder reaction of a derivative of the readily available natural product R-(-)-carvone. Our studies should lead to a short, general route to this class of compounds, suitable for the synthesis of various potentially active analogs. We will also utilize the epoxide fragmentation chemistry in a total synthesis of the triquinane natural products, (-)-delta9(12)-capnellene and (+)- hirsutene, as well as the tricyclic furan-containing terpene, furoscrobiculin D. Tactically, these syntheses differ significantly from one another and, in addition to being highly efficient, are designed so that each will provide insight on chemical reactivity.